The long-term goal is to elucidate the functions of hamartin and tuberin. Specific Aims include 1) to identify the germline "first hit" and somatic "second hit" mutations in TSC-associated renal cell carcinomas, 2) to identify other somatic genetic events involved in the development of renal cell carcinoma in TSC patients, 3) to define the hamartin-tuberin interaction domain and to determine the effects of naturally occurring mutations on the hamartin-tuberin interaction, and 4) to determine the role of hamartin in cell cycle regulation.